Discovery and Optimizationof Novel NonhydroxamateLpxC Inhibitors for the Treatment of Multidrug-Resistant Gram-NegativeInfections

This report summarizes the discovery and optimization of a novel series of nonhydroxamate inhibitors targeting LpxC, a Zn2+-dependent hydrolase that is essential for the survival of Gram-negative bacteria. Beginning with a 5-hydroxypyrimidin-4-one metal-binding pharmacophore, structure-based approaches were utilized to generate a series of potent inhibitors that exhibited activity against a wide variety of Enterobacterales, including both susceptible and multidrug-resistant pathogens, and efficacy in murine thigh infection models. These novel compounds were evaluated in a rat model of cardiovascular toxicity to demonstrate the safety of the scaffold relative to another LpxC inhibitor that proved unsuccessful in Phase I clinical trials. A variety of inhibitors with potent in vivo efficacy and no hemodynamic effects were identified, which constituted an initial suite of potential development candidates.